title: Complementing insulin therapy to achieve glycemic control.
abstract: BACKGROUND
  Most patients with type 2 diabetes mellitus (T2DM) will need incrementally more complex therapeutic regimens to control hyperglycemia as the disease progresses. Insulin is very effective in reducing hyperglycemia and may improve β-cell function in patients with T2DM. However, insulin therapy is associated with weight gain and increased risk of hypoglycemia. Adding other antidiabetes medications to insulin can improve glycemic control and potentially lower the required insulin dose, resulting in less weight gain and lower risk for hypoglycemia. This article summarizes the advantages and disadvantages of different classes of commonly used antidiabetes agents, with emphasis on newer classes, for use as add-on therapy to insulin in patients with T2DM inadequately controlled on insulin therapy.
  
  
  METHODS
  A PubMed search from July 1, 2003 to April 15, 2013 for peer-reviewed clinical and review articles relevant to insulin combination or add-on therapy in T2DM was conducted. Search terms included "insulin combination therapy," "add-on therapy diabetes," "dipeptidyl peptidase-4 (DPP-4) inhibitors," "glucagon-like peptide-1 (GLP-1) receptor agonist," "sodium-glucose cotransporter 2 (SGLT2) inhibitors", "insulin metformin," "insulin sulfonylurea," and "insulin thiazolidinedione." Bibliographies from retrieved articles were also searched for relevant articles. Study design, clinical relevance, and effect on insulin combination therapy were analyzed.
  
  
  RESULTS
  Therapies used as add-on to insulin include agents associated with weight gain (thiazolidinediones and sulfonylureas) and/or hypoglycemia (sulfonylureas), which, therefore, may exacerbate risks already present with insulin. GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors improve glycemic control when added to insulin and have a low propensity for hypoglycemia and cause no change (DPP-4 inhibitors) or a reduction (GLP-1 receptor agonists, SGLT2 inhibitors) in body weight.
  
  
  CONCLUSIONS
  GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors improve glycemic control when combined with insulin. They also have low propensity for weight gain and hypoglycemia and so may be preferred treatment options for insulin combination when compared with traditional therapies.
authors.affiliation: Diabetes Centre, Birmingham Heartlands Hospital, Birmingham B9 5SS, UK. Anthony.barnett@heartofengland.nhs.uk
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Barnett
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D004359:Drug Therapy, Combination / Q000379:methods; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use*; D008687:Metformin / Q000627:therapeutic use; D018027:Receptors, Glucagon / Q000819:agonists; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D018027:Receptors, Glucagon; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D008687:Metformin